Journal of Affective Disorders 283 (2021) 179–191

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review article

Childhood Trauma in Adult Depressive and Anxiety Disorders: An

Integrated Review on Psychological and Biological Mechanisms in the
NESDA Cohort
Erika Kuzminskaite a, *, Brenda W.J.H. Penninx a, Anne-Laura van Harmelen b, c, d,
Bernet M. Elzinga c, e, Jacqueline G.F.M. Hovens f, Christiaan H. Vinkers a, g
a
Department of Psychiatry (GGZ inGeest), Amsterdam UMC (location VUmc), Vrije University, Amsterdam Public Health and Amsterdam Neuroscience Research
Institutes, Amsterdam, the Netherlands
b
Department of Education and Child Studies, Leiden University, Leiden, the Netherlands
c
Leiden Institute for Brain and Cognition (LIBC), Leiden University, Leiden, the Netherlands
d
Department of Psychiatry, University of Cambridge, Cambridge, UK
e
Institute of Psychology, Clinical Psychology Unit, Leiden University, Leiden, the Netherlands
f
Department of Psychiatry, Leiden UMC, Leiden, the Netherlands
g
Department of Anatomy and Neurosciences, Amsterdam UMC (location VUmc), Vrije University, Amsterdam, the Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Childhood trauma (CT) has adverse consequences on mental health across the lifespan. The un­
Childhood trauma derstanding of how CT increases vulnerability for psychiatric disorders is growing. However, lack of an inte­
Childhood maltreatment grative approach to psychological and biological mechanisms of CT hampers further advancement. This review
Depression, anxiety
integrates CT findings across explanatory levels from a longitudinal adult cohort – the Netherlands Study of
Review
Depression and Anxiety (NESDA).
Methods: We reviewed all studies (k = 37) from the NESDA cohort (n = 2981) published from 2009 to 2020
containing CT findings related to psychopathology and potential psychological and biological mechanisms of CT.
Results: CT was associated with a higher risk of anxiety and depressive disorders with the strongest associations in
the comorbid group. CT predicted the onset of these disorders, recurrence, and poorer outcomes (more co­
morbidity and chronicity). CT was associated with maladaptive personality characteristics and cognitions (e.g.,
higher neuroticism and negative self-associations), mild stress systems dysregulations (heightened levels of
cortisol and inflammation), advanced biological aging (increased epigenetic aging and telomere attrition), poorer
lifestyle (higher smoking rate and body mass index), somatic health decline (e.g., increased metabolic syndrome
dysregulations), and brain alterations (e.g., reduced mPFC volume and increased amygdala reactivity).
Limitations: Literature review of one cohort using mixed analytical approaches.
Conclusion: : CT impacts the functioning of the brain, mind, and body, which together may contribute to a higher
vulnerability for affective disorders. It is essential to employ an integrative approach combining different sources
of data to understand the mechanisms of CT better.

1. Introduction "all forms of physical and/or emotional ill-treatment, sexual abuse,

neglect or negligent treatment or commercial or other exploitation,
Childhood trauma (CT) is one of the most robust and significant risk resulting in actual or potential harm to the child’s health, survival,
factors for depressive and anxiety disorders. CT is commonly defined as development or dignity in the context of a relationship of responsibility,

* Corresponding author at: Department of Psychiatry (GGZ inGeest), Amsterdam UMC (location VUmc), Vrije University, Oldenaller 1, 1081 HJ, Amsterdam, the
Netherlands.
E-mail addresses: e.kuzminskaite@ggzingeest.nl (E. Kuzminskaite), b.penninx@amsterdamumc.nl (B.W.J.H. Penninx), a.van.harmelen@fsw.leidenuniv.nl
(A.-L. van Harmelen), elzinga@fsw.leidenuniv.nl, a.van.harmelen@fsw.leidenuniv.nl (B.M. Elzinga), j.g.f.m.hovens@lumc.nl (J.G.F.M. Hovens), c.vinkers@
amsterdamumc.nl (C.H. Vinkers).

https://doi.org/10.1016/j.jad.2021.01.054
Received 29 September 2020; Received in revised form 12 January 2021; Accepted 23 January 2021
Available online 28 January 2021
0165-0327/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
E. Kuzminskaite et al.
trust or power" [(World Health Organization (WHO) 1999), p.15]. CT is
operationalized as emotional (or psychological) abuse, physical abuse,
sexual abuse, and neglect (emotional or physical) before the age of 18
years (Butchart et al., 2006). There is uncertainty about the frequency
and severity of CT worldwide, as it is mostly hidden and unreported due
to fear, stigma, and societal acceptance of this type of violence (Pin­
heiro, 2006). Discrepancies between CT rates reported by
child-protection agencies and community studies (self-report) suggest
that most incidences of CT are underreported (Gilbert et al., 2009,
Sedlak and Ellis, 2014). So far, sexual and physical abuse in childhood
has been most frequently investigated, while emotional abuse and
neglect the least (Gilbert et al., 2009, Moody et al., 2018). Unfortu­
nately, CT is common in the clinical and general population. For
instance, a recent systematic review on the international lifetime prev­
alence of self-reported CT combining clinical and general population
revealed the rates of emotional abuse of approximately 21.7% in Europe
and 23.9% in North America (Moody et al., 2018).
CT has severe and long-lasting effects on both mental and somatic
health across the lifespan. About one-third of all adult-onset psychiatric
disorders are related to CT (Sedlak and Ellis, 2014), with lifelong effects
on morbidity and mortality (Gilbert et al., 2009, Chen et al., 2016).
Moreover, CT increases the risk of negative life events, suicidality, sleep
problems, and cognitive problems (Angelakis et al., 2019, Norman et al.,
2012, van Harmelen et al., 2010). CT not only affects mental health but
also increases the risk of obesity, diabetes, lung disease, and cardio­
vascular disorders (Widom et al., 2012, Danese and Tan, 2014). For
instance, exposure to CT has not only been associated with three to four
times increased risk for depression and anxiety but also with two to three
times increased risk of adult cancer, respiratory and cardiovascular
disease (Hughes et al., 2017). This is relevant as somatic health gener­
ally receives limited attention within psychiatry, notwithstanding
higher mortality rates and a greatly reduced lifespan. There is increasing
evidence that CT-related affective disorders represent a clinically
distinct subtype of psychopathology (Teicher and Samson, 2013),
characterized by earlier emergence, more severe and recurrent symp­
toms, as well as worse treatment outcomes be it psychotherapy, phar­
macotherapy, or combined treatment (Teicher and Samson, 2013,
Hovens et al., 2012, Miniati et al., 2010, Nanni et al., 2012, Nelson et al.,
2017). Despite the severity and high prevalence of CT across affective
disorders, it is largely unknown why and how CT is associated with
persistently poor outcomes for both anxiety and depression, and no
targeted treatments exist that reverse the detrimental effects of CT. CT
is, therefore, a major public health problem, and arguably the most
potent predictor of poor mental health across the lifespan.
Biological research findings suggest that severe stress in early life
elevates cortisol levels that over-activate glucocorticoid receptor (GR).
The consequence of this glucocorticoid overproduction during early life
is the abnormal development of the stress systems (Lupien et al., 2009,
Roberts and Lopez-Duran, 2019, van Bodegom et al., 2017). Although
this response may be adaptive in the short-term, it comes at the cost of
long-term maladaptation: a reduced capacity to adequately and
dynamically respond to stress across the lifespan (McLaughlin et al.,
2010, Daskalakis et al., 2013). Precise mechanisms of CT, leading to
poorer outcomes across the lifespan are heterogeneous, spanning from
psychological, environmental to the biological. Unraveling the mecha­
nisms through which CT impacts mental health outcomes so far has been
difficult, due to the methodological heterogeneity among the studies
and the focus on one type of the mechanism. Hence, this review aims to
summarize and integrate CT findings from a large longitudinal adult
sample - The Netherlands Study of Depression and Anxiety (NESDA), in
relation to psychopathology and discuss different psychological and
biological mechanisms that may underlie the long-lasting impact of CT.
2. The Netherlands Study of Depression and Anxiety (NESDA)
The Netherlands Study of Depression and Anxiety (NESDA;
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Journal of Affective Disorders 283 (2021) 179–191
n = 2981) is an ongoing longitudinal cohort study examining the course
and consequences of depressive and anxiety disorders (Penninx et al.,
2008). NESDA sample includes Dutch-fluent adults between 18 and 65
years old with a current or remitted depressive and/or anxiety disorder
(78% Composite International Diagnostic Interview, CIDI) (Robins et al.,
1988) and healthy controls (22%). Participants were recruited between
September 2004 and February 2007 from three different settings:
community (19%), primary health-care (54%), and specialized mental
health-care (27%). Individuals with a primary clinical diagnosis of other
psychiatric disorders, such as post-traumatic stress disorder, bipolar
disorder, psychotic disorder, or obsessive-compulsive disorder, were
excluded. All participants were assessed on various sociodemographic,
lifestyle, (mental) health, and biological factors during a 4-hour clinic
visit. A subgroup of NESDA participants (n = 301) with or without
(healthy controls) depressive and/or anxiety disorder underwent mag­
netic resonance imaging (MRI) assessment at the baseline. These in­
dividuals aged between 18 and 55 years and had no history of major
internal or neurological disorders. NESDA protocol was approved by the
ethical review board of each participating research center in Amster­
dam, Leiden, and Groningen. All participants provided written informed
consent. More detailed information on NESDA can be found in Penninx
et al. (Penninx et al., 2008).
Within NESDA, CT was examined in 37 articles (identified from the
list of all publications to date on the NESDA website: www.nesda.nl)
focused on psychopathology as well as potential psychological and
biological mechanisms underlying CT. Exposure to CT in NESDA was
assessed twice: at the baseline using the structured Childhood Trauma
Interview (CTI) (de Graaf et al., 2004), and at a 4-year follow-up using
the self-reported Childhood Trauma Questionnaire-Short Form
(CTQ-SF) (Bernstein et al., 2003). Both the CTI and the CTQ-SF retro­
spectively assess different types of CT: emotional neglect, emotional
abuse, physical abuse, sexual abuse, and/or physical neglect (addition­
ally assessed by the CTQ-SF) before the age of 16, thus, while growing
up. The strong correlation between the CTI and the CTQ-SF with a 4-year
time difference (total score, r = 0.77; subscales, r = 0.57-0.61) indicated
high consistency of retrospective reports (Kuzminskaite et al., 2020,
Spinhoven et al., 2014). Due to the fact that it was assessed at the
baseline and had the largest completeness (99.6%), the majority of
research within NESDA focuses on the CTI. In the CTI, each CT type is
answered as "no" or "yes" with a further frequency indication as (0) -
"never", (1) - "once or sometimes", and (2) - "regularly, often, or very
often" (range 0-2). In the case of CT, participants are asked about the
perpetrator: biological father, biological mother, stepfather or friend of
the mother, stepmother or friend of the father, siblings, other family
member, or somebody else. Intercorrelations between different CT types
ranged from modest to large, with the highest correlation between
emotional neglect and emotional abuse (r = .61, p < .001) (see Fig. 1 for
correlations and density plots). Hence, the sum of the number of CT
types and frequency of exposure to CT (childhood trauma index, range
0-8) is often used as a gradient and has been particularly associated with
the prevalence, chronicity, and development of psychopathology in a
dose-response manner (Hovens et al., 2012, Hovens et al., 2010,
Wiersma et al., 2009, Hovens et al., 2015).
3. Epidemiological Findings of CT Within NESDA
3.1. CT Prevalence and Impact on Affective Disorders
Concerning the prevalence rates of CT within NESDA (n = 2970;
exposure of at least once as assessed by the CTI), emotional neglect and
emotional abuse were the most common types (38.9% and 24.8%,
respectively), followed by sexual (18.5%) and physical abuse (13.8%)
with approximately half of participants (48.6%) having experienced at
least one type of CT. Out of participants with CT, the majority scored in
the mild childhood trauma index range (score 1-3; 55.5%), with 44.5%
scoring in the more severe range (score ≥ 4). If emotional neglect or
E. Kuzminskaite et al.
Fig. 1. Scaled density plots for childhood trauma index and each trauma type with corresponding intercorrelations (Pearson’s r).
Note: all correlation p-values < .001
emotional abuse were present, more than 80% reported the frequency of
"regularly, often, or very often". This was lower for physical (52%) and
sexual abuse (23.3%). Emotional neglect, emotional abuse, and physical
abuse were most often identified as perpetrated by family members (61-
84%), while sexual abuse by someone else (71%). For additional details,
also see Hovens et al. (Hovens et al., 2010).
Many previous studies that reported a relationship between CT and
depressive or anxiety disorders in adulthood have focused on lifetime
psychopathology (Kessler et al., 1997) and the more obvious forms of
maltreatment, such as physical and sexual abuse. Within NESDA, the
emphasis was on multiple types of CT (i.e., emotional neglect,
emotional, physical, and sexual abuse), and the specificity of associa­
tions with psychopathology (depressive versus anxiety disorders)
(Hovens et al., 2010). In a sample of 1931 participants, we demonstrated
that exposure to any type of CT was associated with a higher risk of
current anxiety and depressive disorders in increasing strength from
current anxiety to current depressive to current comorbid disorder
(OR = 2.3, 4.8, and 9.4, respectively, for CT score 4-8 versus 0). All types
of CT were also consistently and strongly associated with the presence of
current anxiety and depressive disorders in adulthood. These findings
concurred with a previous meta-analysis (Norman et al., 2012) and
showed robust evidence of the impact of emotional neglect, emotional
and physical abuse on the presence of depressive and anxiety disorders
in adulthood according to a robust dose-response gradient. For all CT
types, strongest associations were found in the comorbid group. Since
comorbidity is associated with an increased number and severity of
symptoms, our results suggest that CT contributes to the severity of
psychopathology. Childhood life events (i.e., divorce of parents, early
parental loss, and placement in care) were not consistently associated
with psychopathology (Hovens et al., 2010).
Some studies have additionally analyzed associations between
different types of CT and various depressive and anxiety disorders,
suggesting that different trauma types may be linked to somewhat
different psychopathology manifestations (van Veen et al., 2013,
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Journal of Affective Disorders 283 (2021) 179–191
Spinhoven et al., 2010). Although all CT types were significantly asso­
ciated with almost all depressive and anxiety disorders (i.e., dysthymia,
major depressive disorder (MDD), generalized anxiety disorder, social
phobia, panic disorder, agoraphobia), when controlled for comorbidity
of disorders and different trauma types, emotional neglect appeared to
be particularly associated with dysthymia, MDD, and social phobia,
while sexual abuse with dysthymia only (Spinhoven et al., 2010).
Adjusting for CT types and psychopathology status, emotional neglect
was also found to be independently associated with the general distress
and anhedonic depression symptom profiles, while sexual abuse with
the general distress and anxious arousal (van Veen et al., 2013). These
findings suggest that maltreatment, especially, emotional neglect, seem
to be stronger associated with manifestations of depression.
Moreover, CT often occurs within families, and recently also siblings
of respondents with lifetime depression and/or anxiety were invited to
participate in the NESDA study. In a subsample consisting of 256 fam­
ilies (n = 636), siblings showed the most similarity in their reports of
emotional abuse and/or emotional neglect followed by physical abuse,
whereas sexual abuse was mostly reported by one person within a family
(Kullberg et al., 2020). In line with these observations, the mean family
level of emotional maltreatment and physical abuse, but not sexual
abuse, were associated with more depressive symptoms. Hence, partic­
ularly in the case of more visible forms of CT, findings implicate that in
addition to individual maltreatment experiences, the context of siblings’
experiences is another crucial risk factor for adult depressive
symptomatology.
3.2. CT and the Course of Affective Disorders
Exposure to CT as a predictor of the 2-year course of depressive and
anxiety disorders was studied in a follow-up sample of 1209 NESDA
participants with a baseline diagnosis of depressive and/or anxiety
disorder (Fig. 2) (Hovens et al., 2012). The results confirmed that a re­
ported history of CT was associated with a poor outcome, characterized
E. Kuzminskaite et al.
Fig. 2. The impact of childhood trauma on the 2-year course of depressive and/or anxiety disorders within the NESDA cohort with (1) and without (2) psycho­
pathology at the baseline (see also: Hovens et al. (2012). Impact of childhood life events and trauma on the course of depressive and anxiety disorders. Acta Psychiatr
Scand, 126(3), 198-207; Hovens et al. (2015). Impact of childhood life events and childhood trauma on the onset and recurrence of depressive and anxiety disorders.
J Clin Psychiatry, 76(7), 931-938).
*p < .001
by more comorbidity and chronicity (Wiersma et al., 2009, De Venter
et al., 2017). This prospective study was different from the handful of
previous studies in terms of considerably larger sample size and the
inclusion of a range of CT types. We found that childhood emotional
neglect, emotional abuse, and physical abuse were all (consistently and
strongly) associated with the persistence of both depressive and co­
morbid depressive and anxiety disorders. Emotional neglect and
emotional abuse were also associated with a higher occurrence of a
chronic course. No significant associations were found between child­
hood sexual abuse and the course of anxiety and depressive disorders,
which was surprising and counter-intuitive. This could partially be
attributed to a somewhat lower statistical power for sexual abuse when
compared to emotional neglect and abuse. The CT score was predictive
of both depressive or comorbid disorder and a chronic course after a
2-year follow-up. The impact of CT on diagnostic status and course at a
2-year follow-up was not as strong for anxiety disorders.
Additionally, we explored the differential impact of different types of
CT on the onset or recurrence of anxiety, depressive, and comorbid
disorders in a sub-sample of 1167 NESDA participants without current
baseline depressive and/or anxiety disorder followed over a 2-year time
period (Fig. 2) (Hovens et al., 2015). Prospective evidence of CT pre­
dicting onset and recurrence of adult affective disorders is scarce and
limited to children samples followed until (young) adulthood (Widom
et al., 2007, Moffitt et al., 2007, Clark et al., 2010). We found that a
history of CT significantly predicted the first onset and recurrence of
depressive and comorbid disorders, but only slightly increased the risk
for anxiety disorders. Among the CT types, emotional neglect was the
main independent predictor of first onset and recurrence of any
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Journal of Affective Disorders 283 (2021) 179–191
depressive or comorbid disorder at 2-year follow-up, suggesting that the
relationship between CT and psychopathology is predominantly driven
by emotional neglect. In line with NESDA previous cross-sectional
studies (Hovens et al., 2010, Spinhoven et al., 2010), childhood life
events were not associated with the 2-year onset and recurrence of
depressive and/or anxiety disorders. Our findings on the course of
depression in adults with reported CT were confirmed in a meta-analysis
(Nanni et al., 2012), suggesting that maltreated individuals were twice
more likely to develop both recurrent and persistent depressive episodes
than those without a history of maltreatment. Altogether, NESDA find­
ings indicate that individuals with the history of CT are at particular risk
for depressive disorders and comorbid depression-anxiety, which
further results in the personal and societal burden. For instance, findings
within NESDA showed that individuals with severe childhood trauma
had significantly reduced work functioning in terms of absenteeism and
presenteeism, which was partially explained by current depressive and
comorbid depressive and anxiety disorders (De Venter et al., 2020).
3.3. Psychological Mechanisms Linking CT and Psychopathology
3.3.1. Maladaptive Personality Characteristics and Cognitions
Exposure to CT may alter basic cognitive assumptions about the self
and others, that over time may become ingrained in an individual’s
personality. The Five-Factor Model (FFM), in which individual person­
ality differences are grouped to the five major dimensions of neuroti­
cism, extraversion, openness, agreeableness, and conscientiousness,
presently constitutes one of the dominant models comprehensively
examining personality functioning (Kotov et al., 2010). The
E. Kuzminskaite et al.
development of the less adaptive personality characteristics has been
proposed as a potential underlying mechanism explaining the link be­
tween CT and subsequent psychopathology (Kim et al., 2009). In line,
within NESDA, the severity of CT corresponded with more maladaptive
personality characteristics and cognitive reactivity styles, including
higher levels of neuroticism, openness, hopelessness, rumination, and
external locus of control and lower levels of extraversion, agreeableness,
and conscientiousness (Table 1) (Hovens et al., 2016). Specifically,
emotional neglect and abuse were associated with all personality char­
acteristics in a detrimental direction, whereas physical and sexual abuse
predicted only neuroticism, openness, rumination, hopelessness, and
external locus of control (Hovens et al., 2016). Adopting a
person-centered approach to personality, we have also identified five
latent (mal)adaptive personality types, which primarily differed in the
degree of neuroticism, extraversion, and, to a lower extent, conscien­
tiousness and agreeableness with openness to experience not being
related to a personality type (Spinhoven et al., 2016). In line with the
findings by Hovens et al. (Hovens et al., 2016), individuals reporting
more severe CT showed the most maladaptive personality types (Spin­
hoven et al., 2016). Additionally, individuals with high levels of
neuroticism were found to be particularly vulnerable to the impact of
cumulative stress (including CT) on depression outcomes (Vinkers et al.,
2014), suggesting that personality is both a moderator and a potential
mediator of psychopathology.
Within NESDA, CT has also been associated with lower levels of
optimism with emotional abuse and/or emotional neglect showing the
strongest association, even after adjustment for potential confounders
(Broekhof et al., 2015). This is in line with a study among 20,000 Finnish
workers, showing a dose-response association between childhood ad­
versities and optimism (Korkeila et al., 2004). In addition, another
NESDA study investigated the association between different types of
abuse and negative self-associations and found that emotional abuse
and/or emotional neglect, compared to other types of abuse, had the
strongest association with both self-reported and automatic (implicit)
negative self-associations to words such as "useless", "inadequate", or
"insecure" (van Harmelen et al., 2010). One of the explanations for the
particularly strong link between emotional maltreatment and negative
cognitions is that in the case of emotional abuse or emotional neglect,
negative self-associations are explicitly handed to the child by the parent
(e.g., "you are worthless"). Moreover, automatic and explicit negative
self-associations partially mediated the link between emotional abuse
and/or neglect and depressive or anxious symptomatology (van Har­
melen et al., 2010), and may also alter emotional regulation strategies
that underlie optimistic outcome expectancies (Rose and Abramson,
1992). Overall, NESDA findings on potential psychological mechanisms
of CT suggest that CT may generate maladaptive personality charac­
teristics, including higher levels of neuroticism and negative
self-associations, as well as lower levels of extraversion and optimism.
3.4. Biological Mechanisms Linking CT and Psychopathology
3.4.1. Dysregulated Biological Stress Systems
Alterations in the activity of the major stress systems, namely, the
hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory
system, and the autonomic nervous system (ANS), are at the center of
the biological psychiatry research seeking to explain the enduring
impact of CT. Stressful life events can irreversibly dysregulate the
functioning of stress systems by chronically stimulating the release of
cortisol, the secretion of pro-inflammatory cytokines, and the alteration
of sympathetic and parasympathetic nervous system activity (Danese
and Baldwin, 2017, Koss and Gunnar, 2018, Young-Southward et al.,
2019). These vital stress systems are also firmly connected by regulating
each other’s functioning, e.g., HPA-axis is involved in the regulation of
inflammatory processes, which in turn stimulate the release of cortisol.
Despite being inconclusive and generally suggesting small additive ef­
fects, a body of evidence indicates dysregulated stress systems as factors,
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Journal of Affective Disorders 283 (2021) 179–191
at least partially explaining the enduring impact of CT (Ioannidis et al.,
2020). Recent meta-analyses confirmed significant associations between
CT and blunted wake-up cortisol as well as cortisol response to experi­
mental social stress conditions (Bernard et al., 2017, Bunea et al., 2017).
Nevertheless, the more static patterns of basal cortisol, cortisol awak­
ening response (CAR), diurnal cortisol slope, or cortisol response to
acute stress were not consistently associated with CT (Bernard et al.,
2017, Fogelman and Canli, 2018). Meta-analytic evidence also
concluded CT as being significantly linked to heightened levels of adult
pro-inflammatory C-reactive protein (CRP), interleukin-6 (IL-6), and
tumor necrosis factor-α (TNF-α) (Baumeister et al., 2016). Evidence on
the autonomic dysregulation is rather inconsistent, but generally sug­
gesting blunted heart rate (HR) and pre-ejection period (PEP) with
inconclusive findings on respiratory sinus arrhythmia (RSA) in response
to experimental psychological stress conditions (Young-Southward
et al., 2019, Sijtsema et al., 2015, Lovallo et al., 2012).
Within NESDA, we not only examined associations between CT and
separate commonly assessed markers of major stress systems, but also
employed an integrative approach including cumulative markers within
each stress system and across all systems (Table 1). Although higher
retrospective CT scores in the NESDA cohort were generally associated
with slightly elevated salivary cortisol and blood inflammation levels,
the number of significant associations was very limited (Kuzminskaite
et al., 2020, Holleman et al., 2012). Regression coefficients were small,
but rather comparable to the effects observed in previous meta-analyses,
both in terms of the direction and the magnitude, somewhat contra­
dicting findings on blunted wake-up cortisol (Bernard et al., 2017,
Fogelman and Canli, 2018, Baumeister et al., 2016). Direct associations
between CT and stress systems within the total NESDA cohort could
have been hard to discern due to the genetic moderation, at least within
the HPA-axis (Gerritsen et al., 2017), or by an overrepresentation of
psychopathology, characterized by significantly dysregulated stress
systems within NESDA (Hu et al., 2016, Vogelzangs et al., 2016, Vree­
burg et al., 2009). Consequently, to increase contrast, we compared
individuals with severe CT (including those with and without psycho­
pathology) to healthy controls without CT, resulting in significantly
elevated levels of the CAR, cumulative HPA-axis markers, CRP, IL-6,
cumulative inflammation, and cumulative stress markers across all
systems, partially explained by unhealthy lifestyle and higher rates of
chronic diseases (Kuzminskaite et al., 2020). Moreover, individuals with
more occurrence of CT showed lower levels of CAR or evening cortisol
when more demands, less control, and less social support at work was
reported (Holleman et al., 2012), suggesting that a history of CT may be
important in how the HPA-axis responds to recent life stress. Taken
together, our findings suggest that the direct impact of CT on stress
systems is small and may be influenced by the presence of psychopa­
thology as well as poorer lifestyle, somatic health, and recent life stress.
3.4.2. Accelerated Biological Aging, Unhealthy Lifestyle, and Somatic
Health Decline
CT not only affects the brain but also extends its effects to poor health
behaviors and the functioning of our entire body. A recent meta-analysis
has shown significant associations between multiple exposures to CT
and poor adult lifestyle behaviors such as physical inactivity, obesity,
smoking, sexual risk-taking, heavy alcohol and illicit drug use (Hughes
et al., 2017). In line, within NESDA, we found that individuals with
severe CT had significantly higher rates of smoking and body mass index
(BMI) than healthy controls without CT (Table 1) (Kuzminskaite et al.,
2020). This was also true when comparing those with and without CT
whilst not excluding psychopathology, suggesting lifestyle as an essen­
tial factor for understanding the impact of CT on health outcomes.
Moreover, meta-analytic findings on 38 studies confirmed that in­
dividuals with retrospectively reported CT showed a 40% increased risk
of adult cardiometabolic disease, consisting of cardiovascular diseases,
diabetes, and metabolic syndrome (Jakubowski et al., 2018). In line
with these findings, within NESDA, we found that individuals with CT,
E. Kuzminskaite et al. Journal of Affective Disorders 283 (2021) 179–191

Table 1
Studies examining CT-related personality characteristics, cognitions, stress systems’ functioning, biological aging, lifestyle, and somatic health in the NESDA cohort.
Study Focus Sample CT Outcome

Personality Characteristics and Cognitions

van Harmelen Negative self-associations n = 2483 of which CTI: multiple incidences per trauma CT was associated with (implicit and explicit) enhanced
et al. (2010) 48.3% with CT type, and any trauma negative self-associations. When compared to physical
and sexual abuse, emotional abuse and/or neglect had
the strongest link to negative self-associations.
Vinkers et al. Neuroticism n = 2274 of which CTQ-SF and CTI: total severity scores of The impact of the cumulative stress index, including CT
(2014) ~45% with CT any trauma (as a part of the cumulative and other stressors, on depression, was most
stress index including CT, major life pronounced in vulnerable individuals with high levels
events, and daily hassles) of trait neuroticism.
Broekhof et al. Optimism n = 2104 of which CTI: a sum of trauma frequency per CT CT was associated with lower levels of optimism with
(2015) ~45% with CT type (range 0-2) emotional abuse and/or neglect showing the strongest
association.
Hovens et al. Personality characteristics n = 1474 of which CTI: a sum of trauma frequency per CT CT was associated with lower levels of extraversion,
(2016) and cognitive reactivity 57.4% with CT type (range 0-2), and a total sum of the agreeableness, and conscientiousness, and higher levels
styles number and frequency of any trauma of neuroticism, openness, hopelessness, rumination,
(range 0-8) and external locus of control. Emotional neglect and
abuse were associated with all personality
characteristics in detrimental direction, whereas
physical and sexual abuse predicted only neuroticism,
openness, rumination, hopelessness, and external locus
of control.
Spinhoven et al. Maladaptive personality n = 2938 of which CTI: multiple incidences per CT type, and CT severity was progressively associated with more
(2016) types 44.5% with CT a total sum of the number of trauma maladaptive personality types. Prevalence rates of CT
(range 0-4) types were higher at higher levels of maladaptive
personality functioning.
Biological Stress Systems
Holleman et al. Salivary cortisol n = 1995 of which CTI: multiple incidences of any type of CT was not associated with saliva cortisol levels. Those
(2012) ~45% with CT trauma, and a total sum of the number reporting higher scores of total CT had a lower CAR or
and frequency of any trauma (range 0-8) evening cortisol levels when reporting more demands,
less control or less social support at work.
Gerritsen et al. HPA-axis genes, salivary n = 2327 of which CTI: a total sum of the number and NR3C2 gene (which codes for MR) AA (vs. G) allele
(2017) cortisol, hippocampal and 50% with CT frequency of any trauma (range 0-8) carriers with CT showed higher cortisol levels after
amygdala volume DST.
Kuzminskaite Salivary cortisol, blood n = 2778 of which CTI: a sum of trauma frequency per CT No consistent associations between CT and cortisol,
et al. (2020)* inflammatory markers, and 47.9% with CT type (range 0-2), and a total sum of the inflammation, or autonomic activity in the total sample.
ANS activity number and frequency of any trauma Those with severe CT as compared to healthy controls
(range 0-8); without CT showed the strongest evidence for slightly
CTQ-SF: total severity scores elevated levels of cortisol, inflammation, and
cumulative stress systems’ markers, partially explained
by an unhealthier lifestyle and poorer health.
Biological Aging, Lifestyle, and Somatic Health
van Reedt Metabolic risk factors n = 2755 of which CTI: a sum of trauma frequency per CT Sexual, emotional, and physical abuse were associated
Dortland et al. ~45% with CT type (range 0-2) with lower levels of HDL cholesterol, higher waist
(2012) circumference, and overall increased metabolic risk.
Emotional neglect was associated with lower SBP.
Sexual abuse was the most unfavorable correlate of
metabolic risk.
Verhoeven et al. Telomere length n = 1095 with current CTI: a total sum of the number and CT was not associated with telomere length in
(2014) MDD from n=2407 of frequency of any trauma (range 0-8) individuals with current MDD.
which ~45% with CT
Verhoeven et al. Telomere length n = 2936 of which CTI: a sum of trauma frequency per CT CT was not associated with shorter telomere length.
(2015) ~45% with CT type (range 0-2), and a total sum of the
number and frequency of any trauma
(range 0-8);
CTQ-SF: total severity scores
Bomhof-Roordink Subclinical cardiovascular n = 650 of which CTI: a sum of trauma frequency per CT Increased central arterial stiffness was found in
et al. (2015) disease 47.5% with CT type (range 0-2), and a total sum of the individuals with CT, especially in those with highest
number and frequency of any trauma trauma score. Severity of depression and anxiety
(range 0-8) partially mediated this association. All CT types, except
sexual abuse, showed significant associations with
increased central arterial stiffness.
Generaal et al. Musculoskeletal pain n = 1646 of which CTI: a total sum of the number and CT was associated with both the presence and the
(2016) ~45% with CT frequency of any trauma (range 0-8) severity of chronic pain. Associations remained
significant after depression, anxiety, and antidepressant
adjustment.
Révész et al. Telomere attrition n = 1860 of which CTI: a total sum of the number and Higher baseline CT score predicted larger 6-year
(2016) ~45% with CT frequency of any trauma (range 0-8) telomere attrition.
Han et al. (2018) DNA methylation n = 811 with current CTI: a total sum of the number of any CT was positively associated with epigenetic aging in
MDD from 1130 of trauma (range 0-4) individuals with current MDD.
which ~45% with CT
Kuzminskaite Smoking and BMI n = 2778 of which CTI: a total sum of the number and Individuals with severe CT had significantly higher
et al. (2020)* 47.9% with CT frequency of any trauma (range 0-8) rates of smoking and BMI than healthy controls without
CT.

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E. Kuzminskaite et al.
Note. * Same study.
Abbreviations: ANS, autonomic nervous system; BMI, body mass index; CT, childhood trauma; CTI, childhood trauma interview; CTQ-SF, childhood trauma
questionnaire-short form; CAR, cortisol awakening response; DST, dexamethasone test; HDL, high-density lipoprotein; MDD, major depressive disorder; MR,
mineralocorticoid receptor; SBP, systolic blood pressure.
especially those with severe CT, showed more subclinical cardiovascular
disease symptoms as represented by the increased central arterial stiff­
ness (Bomhof-Roordink et al., 2015). Exposure to CT, especially sexual
abuse, was also associated with more metabolic syndrome dysregula­
tions when compared to no CT exposure (van Reedt Dortland et al.,
2012). These results were most clearly present for dyslipidemia and
abdominal obesity, but not for hypertension and hyperglycemia com­
ponents of the metabolic syndrome. Results could not be explained by a
poorer lifestyle (e.g., smoking, alcohol use, or physical inactivity) in
individuals with CT. The adverse health effect of CT is not limited to
cardiovascular outcomes. In addition, within NESDA, CT has also been
associated with more presence and severity of chronic musculoskeletal
pain (Generaal et al., 2016).
Observational research shows that exposure to adverse childhood
events leads to dramatically different life-course trajectories, including a
two-times higher risk for premature mortality but also the increased
onset of various somatic conditions (Bellis et al., 2013). Consequently,
CT seems to be more generally linked to an increased risk for age-related
health conditions. This leads to the suggestion that CT can more
generally accelerate the aging process. Although chronological age is
invariable, people differ in biological age, which may fall behind or
outpace chronological age. Biological aging is a multi-faceted and
complex process that manifests across multiple levels. Therefore, there is
no single indicator that captures biological aging completely; multiple
indicators exist (Han et al., 2019). Examples of molecular indicators of
biological age are short telomere length, decrease in mitochondrial
deoxyribonucleic acid (DNA) copy number, and more advanced epige­
netic, transcriptomic, or metabolomic age. Within NESDA, we measured
epigenetic aging (via sequencing of all DNA methylation sites) and
telomere length (via quantitative polymerase chain reaction). Both DNA
methylation and telomere length showed more accelerated aging in
depressed individuals versus controls (Han et al., 2018, Verhoeven et al.,
2016, Verhoeven et al., 2014). As compared to controls, most advanced
epigenetic aging was present in depressed individuals with CT (Han
et al., 2018). Although cross-sectionally CT was not associated with
telomere length (Verhoeven et al., 2014, Verhoeven et al., 2015), more
considerable telomere attrition from baseline to 6-year follow-up was
found to be present in individuals with more severe CT (Révész et al.,
2016). Overall, these NESDA findings support the hypothesis that CT
may produce long-lasting biological "scars" that have an impact on
advanced or premature aging processes later in life.
3.4.3. Altered Brain Structure and Function
CT has been hypothesized to alter brain development via sustained
activation of the HPA-axis and the immune system. During stress, the
sympathetic nervous system activates immune cells to stimulate the
release of the pro-inflammatory markers (Pongratz and Straub, 2014).
As such, chronic activation of the HPA-axis and immune system are
thought to be one of the mechanisms through which CT may impact on
the structure and function of the brain (Danese and Baldwin, 2017,
Danese and van Harmelen, 2017).
Structural MRI studies. Within NESDA, studies on brain structure
(Table 2) have predominantly focused on key emotional brain regions
(medial prefrontal cortex, mPFC), the limbic regions (hippocampus and
amygdala), and conducted exploratory whole-brain analyses. The find­
ings showed reduced dorsal mPFC volume in both patients and healthy
controls with emotional abuse and/or emotional neglect (van Harmelen
et al., 2010). This is in line with a review suggesting that CT-related
mPFC reductions may not be directly related to vulnerable emotional
functioning (Moreno-López et al., 2019). Indeed, we observed that pa­
tients with CT reported significantly more negative life events than
185
Journal of Affective Disorders 283 (2021) 179–191
healthy controls with CT, which may, in turn, lead to depressive and
anxiety disorders (van Harmelen et al., 2010). While reduced amygdala
volume was linked to CT, hippocampal and anterior cingulate cortex
(ACC) volumes were not directly related to CT in the NESDA sample (van
Harmelen et al., 2010, Molendijk et al., 2012, Gerritsen et al., 2015, van
Velzen et al., 2016). However, there were additional indications that
genetic influences may play a role in reducing amygdala, ACC, and
hippocampal volumes for individuals with CT (see the section below)
(Gerritsen et al., 2017, Molendijk et al., 2012, van Velzen et al., 2016).
The hippocampal effects may contribute to increased vulnerability to
the development of psychopathology in the NESDA sample; as Gerritsen
et al. (Gerritsen et al., 2015) showed that in those individuals with CT, a
diagnosis of MDD was associated with smaller hippocampal volume.
Functional MRI (fMRI) studies. Concerning studies on brain func­
tion (Table 2), individuals reporting emotional abuse and/or emotional
neglect showed amygdala hyperresponsivity to emotional faces (van
Harmelen et al., 2013), suggesting persistent vigilance towards the
detection of emotional facial expressions. CT was associated with
hypoactivity in the mPFC during a task that required higher-order
cognitive processing (van Harmelen et al., 2014). Hippocampal activ­
ity during emotional memory was not affected by CT (van Harmelen
et al., 2014), although hippocampal activity to negative emotional
words may be modulated by genetic influences (Molendijk et al., 2012)
as well as CT-related amygdala and posterior cingulate cortex (PCC)
responses to emotional faces (Opmeer et al., 2014). Finally, we exam­
ined emotional brain connectivity during rest using fMRI within the
limbic, salience, and default networks associated with emotion regula­
tion and self-reflective processing and found widespread reductions in
connectivity patterns of these networks related to CT (van der Werff
et al., 2013). For instance, a decrease in connectivity between the right
amygdala and the precuneus in individuals with CT was reported, which
is essential for emotion regulation and self-reflective processing.
Reduced connectivity with the precuneus within the salience network
may be related to the NESDA findings of more negative self-cognitions in
individuals with CT (van Harmelen et al., 2010). In individuals with CT
exposure, but no psychopathology, increased negative connectivity was
found between the dorsal ACC and the lingual gyrus and occipital fusi­
form gyrus (van der Werff et al., 2013), suggesting that in resilient in­
dividuals with CT increased ability to downregulate emotional
processing and responses in verbal declarative memory may play a role,
leading to improved ability to re-appraise negative situations, or recall
positive autobiographical memories (Ioannidis et al., 2020, Askelund
et al., 2019).
In conclusion, findings from the NESDA study indicate that in in­
dividuals with emotional maltreatment reduced mPFC and amygdala
volumes are found, as well as amygdala hyperactivity, mPFC hypo­
activity, and reduced connectivity in limbic, salience, and default-mode
networks.
3.4.4. Is Everyone Similarly Vulnerable to the Impact of CT?
Although CT is a major risk factor for depression and anxiety,
considerable heterogeneity exists in outcomes after exposure to CT.
Several theories posit that the impact of CT may be dependent on in­
dividual characteristics. However, these characteristics are generally
difficult to identify due to methodological heterogeneity and lack of
replicated findings.
Within NESDA, some individuals seemed to be particularly more
vulnerable to the impact of CT. First, the impact of a cumulative stress
index, including CT and other stressors, on depression was most pro­
nounced in at-risk individuals with high levels of neuroticism (Vinkers
et al., 2014), suggesting that the adverse effects of CT may primarily
E. Kuzminskaite et al. Journal of Affective Disorders 283 (2021) 179–191

Table 2
Studies examining CT-related brain structure and function in the NESDA cohort.
Study Paradigm Sample CT Approach Outcome

MRI Studies
van Harmelen Structural Emotional abuse/ CTI: multiple ROI: hippocampal, amygdala, mPFC Emotional abuse/neglect was associated with
et al. (2010) neglect, yes (n = 84), incidences of volume + whole brain a reduction in left dorsal mPFC volume,
no (n = 97) emotional abuse independent of gender, psychiatric status, and
and/or emotional other types of abuse. No effects of emotional
neglect abuse/neglect on amygdala or hippocampal
volume.
Molendijk et al. Structural Val66val (n = 103; CTI: a total sum of ROI: hippocampal volume + whole Smaller hippocampal volume in val66met
(2012)* 79% with CT); the number and brain allele carriers. No main effect or moderation
val66met allele frequency of any effect by CT. No effects of the BDNF genotype
(n = 54; 43% with trauma (range 0-8) found in other brain areas.
CT)
Gerritsen et al. Structural n = 262 (50% with CTI: a total sum of ROI: hippocampal volume No main effect of CT on hippocampal volume.
(2015) CT) the number of any In those with CT, a diagnosis of MDD was
trauma (range 0-4) associated with smaller hippocampal volume,
but not in those without CT.
van Velzen et al. Structural CT, yes (n = 146), CTI: at least one type ROI: amygdala and hippocampal CT was associated with lower amygdala
(2016) no (n = 143) of CT volume; rostral and caudal ACC volume. This was more pronounced in
cortical thickness and surface area maltreated BDNF vall66met allele carriers.
Decreased cortical thickness of the ACC in CT
with val/val genotype.
Gerritsen et al. Structural n = 225 (from CTI: a total sum of ROI: amygdala and hippocampal NR3C2 gene (which codes for MR) AA (vs. G)
(2017) n = 2327 with the number and volume allele carriers with CT had smaller
genome data of frequency of any hippocampal and amygdala volumes.
which 50% with CT) trauma (range 0-8)
fMRI Studies
Molendijk et al. Emotional Val66val (n = 103; CTI: a total sum of ROI: hippocampus + whole brain Hippocampal activity to negative and neutral
(2012)* memory 79% with CT); the number and (vs. baseline) word encoding higher in BDNF
encoding and val66met allele frequency of any val66met allele carriers. Hippocampal
retrieval (n = 54; 43% with trauma (range 0-8) encoding activity in response to negative
CT) words was higher in those with CT (vs. no CT)
and interacted with genotype: CT predicted
increased hippocampal activation in those
with val/val allele, but not in met allele
carriers.
van Harmelen Emotional face Emotional abuse/ CTI: multiple ROI: dorsal, ventral mPFC, ACC, and Emotional abuse/neglect was associated with
et al. (2013) processing neglect, yes (n = 60), incidences of amygdala + whole brain enhanced bilateral amygdala reactivity to
no (n = 75) emotional abuse emotional faces in general, and independent
and/or emotional of psychiatric status. No support for
neglect differential mPFC functioning.
van der Werff Resting-state Emotional abuse/ CTI: multiple ROI (seed-based): bilateral amygdala Emotional abuse/neglect was associated with
et al. (2013) functional MRI neglect, yes (n = 44), incidences of (limbic network), bilateral dorsal ACC decreased negative connectivity between the
Psychological no (n = 44) emotional abuse (salience network), and the PCC (DMN) right amygdala and bilateral occipital cortex,
Medicine and/or emotional decreased positive connectivity between right
neglect amygdala and OFC, insular to subcortical
structures, including the hippocampus and
putamen. Decreased negative connectivity
between left dorsal ACC and angular cortex
and precuneus. Decreased positive
connectivity between the left dorsal ACC seed
and a bilateral frontal cluster containing the
mPFC, the paracingulate gyrus, and the
frontal pole. No differences in the left dorsal
mPFC seed in the DMN.
van der Werff Resting-state CT (n = 22), matched CTI: at least one type ROI (seed-based): bilateral amygdala CT was associated with an increase in
et al. (2013) functional MRI controls without CT of CT; (limbic network), bilateral dorsal ACC negative connectivity between left dorsal ACC
Child abuse and (n = 11) CTQ: total severity (salience network) and the PCC (DMN) and the lingual gyrus and the occipital
Neglect score of any trauma fusiform gyrus in the resilient group (healthy
individuals with CT) when compared to the
healthy controls (no psychopathology and no
CT) and when compared to patients with
MDD/anxiety with CT.
Opmeer et al. Emotional face Emotional abuse/ CTI: multiple ROI: amygdala + whole brain Within carriers of the C-allele risk genotype,
(2014) processing neglect, yes (n = 56), incidences of emotional abuse/neglect was associated with
no (n = 62) emotional abuse higher amygdala activation, but did not
and/or emotional influence activation in non-risk carriers. In
neglect the PCC, lower activation was seen in those
with emotional abuse/neglect and the risk
genotype, whereas genotype did not influence
PCC activation in those without trauma.
Those carrying the risk genotype with
experience of emotional abuse/neglect made
a faster gender decision than those without
trauma.
(continued on next page)

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Table 2 (continued )
Study Paradigm Sample CT Approach Outcome

van Harmelen Emotional Emotional abuse/ CTI: multiple ROI: hippocampus, amygdala, dorsal, Dorsal mPFC hypoactivity during encoding
et al. (2014) memory neglect, yes (n = 96), incidences of ventral mPFC, dorsolateral PFC, and and recognition of (subsequently) correctly
encoding and no (n = 98) emotional abuse the dorsal and pregenual ACC + whole recognized positive, negative, and neutral
retrieval and/or emotional brain words in adults with emotional abuse/
neglect neglect.

Note. * Same study.

Abbreviations: ACC, anterior cingulate cortex; BDNF, brain-derived neurotrophic factor; CT, childhood trauma; CTI, childhood trauma interview; CTQ-SF, childhood
trauma questionnaire-short form; DMN, default mode network; DST, dexamethasone test; mPFC, medial prefrontal cortex; MR, mineralocorticoid receptor; MDD,
major depressive disorder; OFC, orbitofrontal cortex; PFC, prefrontal cortex; PCC, posterior cingulate cortex; ROI, regions of interest.

surface in those with personality traits linked to a vulnerability for
psychopathology. Second, maltreated men carrying the CA haplotype of
the mineralocorticoid receptor (MR) showed increased depressive
symptoms, whereas those carrying the CG haplotype showed increased
resilient mental health functioning, indicating important sex-dependent
effects of MR on depression susceptibility following CT (Vinkers et al.,
2015). Third, maltreated individuals who carried the AA allele of the
NR3C2 gene, which codes for MR and mediates rapid cortisol effects in
the limbic structures, showed reduced hippocampal and amygdala vol­
umes as well as increased cortisol levels after the dexamethasone sup­
pression test (Gerritsen et al., 2017). Hippocampal and amygdala
volumes were also reduced in individuals reporting CT with the val66met
genotype of the brain-derived neurotrophic factor (BDNF), playing a
critical role in the neural growth (Molendijk et al., 2012, van Velzen
et al., 2016, Hariri et al., 2003), while the ACC thickness was reduced in
the maltreated individuals carrying the val/val genotype (van Velzen
et al., 2016). Individuals with the BDNF val66met genotype also showed
reduced serum BDNF levels when exposed to CT (Elzinga et al., 2011).
Finally, individuals with BDNF val/val allele were characterized by
increased hippocampal activity to negative emotional words (Molendijk
et al., 2012), while those with C-allele of neuropeptide Y genotype
(NPY) showed particularly increased behavioral responding, higher
amygdala activity, and lower PCC activity in response to emotional faces
(Opmeer et al., 2014).
Drawing firm conclusions about specific genes mentioned above is
difficult, as they show small effects and, therefore, require considerable
sample sizes. Consequently, findings on polygenic risk scores (PRS),
reflecting a sum of the relevant risk alleles representing a cumulative
genetic risk, could provide more conclusive evidence. In line, within
NESDA, the effect of PRS on MDD was significantly increased in the
presence of CT, suggesting that individuals with CT and high PRS are
particularly at risk for developing depression (Peyrot et al., 2014). While
some characteristics of individuals more sensitive to the impact of CT
have been revealed, collaborative research, especially on genetic char­
acteristics, is necessary to replicate findings and allow firmer
conclusions.

Fig. 3. CT-related psychological and biological changes involved in (mental) illness manifestations in the NESDA cohort (Created with BioRender.com).
Note: numbers indicate study reference, i.e. 10 van Harmelen et al. (2010), 15 Hovens et al. (2012), 28 Kuzminskaite et al. (2020), 30 Hovens et al. (2010), 31
Wiersma et al. (2009), 32 Hovens et al. (2015), 34 van Veen et al. (2013), 35 Spinhoven et al. (2010), 37 De Venter et al. (2017), 44 Hovens et al. (2016), 45
Spinhoven et al. (2016), 46 Vinkers et al. (2014), 47 Broekhof et al. (2015), 49 van Harmelen et al. (2010), 61 Holleman et al. (2012), 62 Gerritsen et al. (2017), 63
Hu et al. (2016), 64 Vogelzangs et al. (2016), 65 Vreeburg et al. (2009), 67 Bomhof-Roordink et al. (2015), 68 van Reedt Dortland et al. (2012), 69 Generaal et al.
(2016), 72 Han et al. (2018), 73 Verhoeven et al. (2016), 74 Verhoeven et al. (2014), 75 Verhoeven et al. (2015), 76 Révész et al. (2016), 80 Molendijk et al. (2012),
81 Gerritsen et al. (2015), 82 van Velzen et al. (2016), 83 van Harmelen et al. (2013), 84 van Harmelen et al. (2014), 85 Opmeer et al. (2014), 86 van der Werff et al.
(2013), 87 van der Werff et al. (2013).
Abbreviations: BMI, body mass index; CT, childhood trauma; mPFC, medial prefrontal cortex

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E. Kuzminskaite et al.
4. Discussion
This review summarized and integrated the potential mechanisms
through which CT exerts its adverse effects using findings from the large
longitudinal adult NESDA cohort. NESDA results indicated that CT has a
negative impact on the onset and the course of affective disorders, both
for depression and/or anxiety disorders and their comorbidity. These
findings are in line with a large and convincing body of literature,
showing that CT negatively impacts mental health across the lifespan
and is, therefore, one of the most prominent public health risks for poor
mental outcomes (Angelakis et al., 2019, Norman et al., 2012, Widom
et al., 2012, Danese and Tan, 2014, Hughes et al., 2017). Findings also
suggested existing interindividual differences, with some individuals
exposed to CT being at significant risk for psychopathology or further
biological CT-related alterations.
To better understand who is at risk and, ultimately, develop
personalized (preventative) interventions, it is essential to determine the
mechanisms by which CT exerts its adverse outcomes. Our review sug­
gested a wide range of possible pathways in the psychological and
biological domains (Fig. 3). Specifically, within NESDA, CT was asso­
ciated with more maladaptive personality characteristics and cognitions
(higher levels of neuroticism and negative self-associations; lower levels
of extraversion and optimism), stress systems’ dysregulations (slightly
elevated levels of cortisol and inflammation), advanced biological aging
(accelerated epigenetic aging and telomere attrition over time), poorer
lifestyle (higher rates of smoking and BMI), somatic health decline
(increased metabolic syndrome dysregulations, arterial stiffness, and
musculoskeletal pain), and brain alterations at the structural and func­
tional level (reduced mPFC and amygdala volumes; amygdala hyper­
responsivity and mPFC hypoactivity). CT was also linked to more
negative life events and diminished work functioning, indicating addi­
tional personal and societal burden. From all CT types, emotional abuse
and/or emotional neglect seemed to show the most profound effect.
However, this was mostly true when all types of CT were considered
together.
Our findings demonstrated the complexity of an organism, suggest­
ing that the impact of CT on poor mental health outcomes is probably a
result of a complex interaction of genes, brain processes, environment,
and psychological factors (Teicher and Samson, 2013, Daskalakis et al.,
2013, Ioannidis et al., 2020). Although most findings within NESDA on
CT, impacting the brain, mind, and body, fit well with the key hypoth­
eses and explanatory biological models, we have to be cautious of causal
inferences of the succession of pathways (Danese, 2019, Danese and
McEwen, 2012). It is currently unknown how different systems interact
due to a lack of theoretic underpinnings and comprehensive longitudinal
projects integrating psychological, environmental, and biological fac­
tors in the same samples in the context of CT. For instance, obesity is
likely to mediate CT’s impact on adult inflammation (Miller and Chen,
2010); however, other factors such as HPA-axis functioning are also
likely playing a role in this relationship (Miller and Chen, 2010,
Hewagalamulage et al., 2016). Considering longitudinal findings in
NESDA, baseline maladaptive personality characteristics, predomi­
nantly, neuroticism mediated the relationship between CT and the
course of depressive and anxiety disorders (De Venter et al., 2017,
Hovens et al., 2016, Spinhoven et al., 2016). Most likely, CT results in
increased neuroticism levels, leading to a higher vulnerability to psy­
chopathology (Roy, 2002). However, it may well be that children with
higher neuroticism levels are also more likely to experience and/or
report CT. To disentangle the impact of CT, its potentially pre-existing
factors, and succession of pathways leading to psychopathology,
prospective-longitudinal studies are required. Nevertheless, most
research to date relies on cross-sectional studies or longitudinal studies
with factors such as neuroticism being assessed only at one-time point,
forbidding the inference of change before the CT (Ioannidis et al., 2020,
Moreno-López et al., 2019, Danese, 2019).
To advance our knowledge, there are currently several unmet needs
188
Journal of Affective Disorders 283 (2021) 179–191
in psychiatric research concerning CT and affective disorders: lack of
comprehensive longitudinal projects investigating how multiple systems
interact to result in affective disorders, and how these different in­
teractions sustain and proliferate symptomatology. It is essential to
elucidate the time path between CT, its underlying mechanisms, and
psychopathology, as well as investigate how genes and environment are
both involved in adverse CT outcomes. For instance, parenting behav­
iors can be well affected by the psychiatric state of the parent, resulting
in more CT, especially, emotional maltreatment, and further child risk
for affective disorders (Banyard et al., 2003). Therefore, the increased
risk for psychopathology in individuals with CT may be partially related
to genetic transmission. One valuable method would be to link findings
from epidemiological child/adolescent studies to adult population
studies in line with the ongoing Mood and Resilience in Offspring
(MARIO; www.mario-project.nl) cohort study, investigating intergen­
erational transmission of mood disorders.
The current review has some limitations as it focuses on CT findings
within one – albeit large and well-defined – cohort, and replications of
integrative approaches related to CT are essential. At the same time, this
is also a strength as the findings are comparable since the assessment of
CT and other methodology were homogenous. We, therefore, encourage
other large cohorts to employ a similar approach and integrate different
CT findings from the same cohort. Moreover, we refrained from
analyzing the associations and relations between the different CT find­
ings as publications have used data from various waves, and sometimes
only studied subsamples from the total NESDA cohort. Lastly, NESDA is
an adult cohort with self-reported CT. Hence, it is unknown whether CT
findings in adulthood are comparable to those in childhood and whether
they would be different if CT was assessed prospectively.
This review has shown that CT impacts the functioning of the brain,
mind, and body. All these aspects most likely work together and
contribute to a higher vulnerability for affective disorders across the
lifespan. An integration of mechanistic explanations at different psy­
chological, biological, and environmental levels is essential to better
understand the life-long adverse effects of CT in the context of affective
disorders.
5. Funding
The infrastructure for the NESDA study (www.nesda.nl) is funded
through the Geestkracht program of the Netherlands Organization for
Health Research and Development (ZonMw, grant number: 10-000-
1002) and financial contributions by participating universities and
mental health care organizations (VU University Medical Center, GGZ
inGeest, Leiden University Medical Center, Leiden University, GGZ
Rivierduinen, University Medical Center Groningen, University of Gro­
ningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel
Onderzoekscentrum).
Data Availability Statement
According to European law (GDPR) data containing potentially
identifying or sensitive patient information are restricted; our data
involving clinical participants are not freely available in a public re­
pository. However, data are – under some specifications - available upon
request via the NESDA Data Access Committee (nesda@ggzingeest.nl).
See also our website: www.nesda.nl
CRediT authorship contribution statement
Erika Kuzminskaite: Conceptualization, Visualization, Project
administration, Writing - original draft, Writing - review & editing.
Brenda W.J.H. Penninx: Conceptualization, Methodology, Supervi­
sion, Writing - original draft, Writing - review & editing. Anne-Laura
van Harmelen: Writing - original draft, Writing - review & editing.
Bernet M. Elzinga: Writing - original draft, Writing - review & editing.
E. Kuzminskaite et al. Journal of Affective Disorders 283 (2021) 179–191

Jacqueline G.F.M. Hovens: Writing - original draft. Christiaan H. de Graaf, R., Bijl, R.V., ten Have, M., Beekman, A.T., Vollebergh, W.A., 2004. Rapid onset
of comorbidity of common mental disorders: Findings from the Netherlands Mental
Vinkers: Conceptualization, Supervision, Writing - original draft,
Health Survey and Incidence Study (NEMESIS). Acta Psychiatr Scand 109 (1), 55–63.
Writing - review & editing. https://doi.org/10.1046/j.0001-690x.2003.00222.x.
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